COMBINATION Therapies Including TOCILIZUMAB Decrease the Progression of CLAD: Initial Clinical Experience

Purpose TH17 & IL-6 interactions and detrimental Biologic effects may mediate CLAD / BOS in a murine Lung allograft model and Human LT. TOCILIZUMAB (TCZ), a humanized monoclonal Ab targets the IL-6 receptor subunit alpha (IL-6Rα), preventing binding of IL-6 to both IL-6R and signal transducer glycoprotein 130 complex, hence inhibiting downstream signaling (JAK-STAT). Pertinent to potential therapeutic considerations for CLAD, TCZ decreases circulating PMNs, Monocytes, MIF & TH-17 cells and increases TREG & Regulatory B-Lymphocytes. We review our initial TCZ experience with COMBINATION immunotherapies for CLAD. Methods Review LT recipients who received ≥ 3 mos TCZ (4-8 mg/Kg/month) treatment for CLAD. Analysis: (SPIROM) Linear Regression Slope FEV-1 (mL/month), infection incidence, Single Antigen Flow Cytometry HLA Class I & II Donor-specific ALLO-Antibodies (DSA) and Non-HLA Antibodies (EC-1&2, AT1R). Baseline Interleukin-6 (IL-6) Serum values (Quantitative multiplex assay; ARUP Labs, Inc.) were measured (NL: ≤ 5 pg/mL). Values expressed as (Median ± SD) / Paired T-test. Results N=9 [BLT (4), SLT (4), Lung-Liver (1)]; Ages: 65 (23-75) years; M: F (7:2); Time Post-LT: 28 ± 30.9 mos. [4-102]. CLAD Stages: BOS I (2), II (4), III (2), RAS (1). CLAD therapies: Rabbit ATG (5), Rituximab (1), IVIG (9) + TCZ. Baseline DSA (PRE- treatment): HLA Class I (2), Class II (6) in N=6 patients; EC1&2 (6) and AT1R (1). All DSA were Weak or Moderate MFI ( Conclusion 1. Initial experience suggested COMBINATION therapies for CLAD including TCZ, with different therapeutic targets, can stabilize SPIROM Decline without apparent significant Adverse Effects. 2. DSA HLA Class I & II (